RESUMO
Helicobacter pylori was reported as an important cause of gastritis, and gastric ulcers and CagA oncoprotein-producing H. pylori subgroups were blamed to increase the severity of gastritis. Disparities were reported in that the presence of serum anti-CagA IgA was not parallel with CagA-positive H. pylori cohabitation. We hypothesized that the HLA-DQA1 ~ DQB1 haplotypes in human populations include protective haplotypes that more effectively present immunogenic CagA peptides and susceptible haplotypes with an impaired capacity to present CagA peptides. We recruited patients (n = 201) admitted for gastroendoscopy procedures and performed high-resolution HLA-DQA1 and DQB1 typing. Serum anti-CagA IgA levels were analyzed by ELISA (23.0% positive), and H. pylori was classified as positive or negative in gastric mucosal tissue slides (72.6% positive). The HLA DQA1*05:05 allele (29.1%) and HLA DQB1*03:01 allele (32.8%) were found at the highest frequency among gastritis patients of Turkish descent. In HLA DQA1*05:05 ~ DQB1*03:01 double homozygous (7.3%) and heterozygous (40.7%) haplotype carriers, the presence of anti-CagA IgA decreased dramatically, the presence of H. pylori increased, and the presence of metaplasia followed a decreasing trend. The DQ protein encoded by HLA DQA1*05:05-DQ*03:01 showed a low binding affinity to the CagA peptide when binding capacity was analyzed by the NetMHCIIPan 4.0 prediction method. In conclusion, HLA DQA1 ~ DQB1 polymorphisms are crucial as host defense mechanisms against CagA H. pylori since antigen binding capacity plays a crucial role in anti-CagA IgA production.
Assuntos
Gastrite , Infecções por Helicobacter , Helicobacter pylori , Humanos , Haplótipos , Antígenos HLA-DQ/genética , Cadeias alfa de HLA-DQ/genética , Cadeias beta de HLA-DQ/genética , Gastrite/genética , Infecções por Helicobacter/complicações , Infecções por Helicobacter/genética , Alelos , Peptídeos , Metaplasia , Imunoglobulina A/genética , Frequência do Gene , Cadeias HLA-DRB1RESUMO
Patients with autoimmune gastritis (AIG) have a 13-fold risk of developing type-1 neuroendocrine tumors, whereas the risk for gastric adenocarcinoma is still uncertain. Here we describe the clinicopathologic and molecular features of a series of gastric carcinomas (GC) arising in the context of AIG. A total of 26 AIG-associated GC specimens were collected from 4 Italian Institutions. Immunohistochemistry for MUC1, MUC2, MUC5AC, MUC6, CDX2, HER2, PD-L1, CLDN18, mismatch repair (MMR) proteins, and p53 and EBV-encoded RNA (EBER) in situ hybridization were performed. Histologic and immunohistochemical features were jointly reviewed by 5 expert gastrointestinal pathologists. Next-generation sequencing analysis (TrueSight Oncology 500, Illumina) of 523 cancer-related genes was performed on 19 cases. Most tumors were diagnosed as pT1 (52%) and they were located in the corpus/fundus (58%) and associated with operative link for gastritis assessment stage II gastritis (80.8%), absence of parietal cells, complete intestinal metaplasia, and enterochromaffin-like-cell micronodular hyperplasia. Only 4 (15.4%) GCs were diagnosed during follow-up for AIG. The following histotypes were identified: 20 (77%) adenocarcinomas; 3 (11%) mixed neuroendocrine-non-neuroendocrine neoplasms, and 2 (8%) high-grade solid adenocarcinomas with focal neuroendocrine component, 1 (4%) adenocarcinoma with an amphicrine component. Overall, 7 cases (27%) showed MMR deficiency, 3 (12%) were positive (score 3+) for HER2, 6 (23%) were CLDN18 positive, and 11 (42%) had PD-L1 combined positive score ≥ 10. EBER was negative in all cases. Molecular analysis revealed 5/19 (26%) microsatellite instability (MSI) cases and 7 (37%) tumor mutational burden (TMB) high. The most frequently altered genes were TP53 (8/19, 42%), RNF43 (7/19, 37%), ERBB2 (7/19, 37% [2 amplified and 5 mutated cases]), ARID1A (6/19, 32%), and PIK3CA (4/19, 21%). In summary, AIG-associated GCs are often diagnosed at low stage in patients with longstanding misrecognized severe AIG; they often display a neuroendocrine component or differentiation, have relatively higher rates of MMR deficiency, and TMB high.
Assuntos
Doenças Autoimunes , Gastrite , Neoplasias Gástricas , Humanos , Neoplasias Gástricas/patologia , Neoplasias Gástricas/genética , Masculino , Feminino , Gastrite/patologia , Gastrite/genética , Gastrite/imunologia , Idoso , Pessoa de Meia-Idade , Doenças Autoimunes/genética , Doenças Autoimunes/patologia , Adulto , Adenocarcinoma/genética , Adenocarcinoma/patologia , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/análise , Idoso de 80 Anos ou maisRESUMO
BACKGROUND: Helicobacter pylori eradication therapy based on antimicrobial susceptibility in Vietnamese children currently get low efficiency. There are causes of treatment failure, among host genetic factors namely MDR1 C3435T and CYP2C19 affect the absorption and metabolism of proton pump inhibitors - a crucial component of eradication therapy. The study aimed to investigate the effect of MDR1 C3435T and CYP2C19 genetic polymorphisms on the cure rate. METHODS: 207 pediatric patients with gastritis and peptic ulcer infecting Helicobacter pylori completed the eradication therapy based on antimicrobial susceptibility with proton pump inhibitor esomeprazole. Eradication efficacy was assessed after at least 4 weeks by the urease breath test. MDR1 C3435T genetic polymorphism and CYP2C19 genotype were determined using a sequencing method based on Sanger's principle. RESULTS: Among 207 children recruited in this study, the ratio of CYP2C19 EM, IM, and PM phenotypes was 40.1%, 46.4%, and 16.9%, respectively. The patient with MDR1 3435 C/C polymorphism accounted for 43.0%, MDR1 3435 C/T was 40.1%, and MDR1 3435T/T was 16.9%. The cure rate of Helicobacter pylori infection in patients with CYP2C19 EM genotype was 78.3%; 83.3% of those with the IM genotype, and PM genotype was 96,4% (p = 0.07). Successful eradication rates for Helicobacter pylori were 85.4%, 86.7%, and 68.6% in patients with the MDR1 3435 C/C, C/T, and T/T, respectively (p = 0.02). Multiple logistic regression analysis found that MDR1 C3435T genetic polymorphisms of patients were significant independent risk factors for treatment failure, and CYP2C19 genotype did not affect Helicobacter pylori eradication. CONCLUSIONS: The Helicobacter pylori eradication rates by regimens based on antibiotic susceptibility and esomeprazole were not significantly different between the CYP2C19 phenotypes. The MDR1 C3435T polymorphism is one of the factors impacting Helicobacter pylori eradication results in children.
Assuntos
Subfamília B de Transportador de Cassetes de Ligação de ATP , Citocromo P-450 CYP2C19 , Gastrite , Infecções por Helicobacter , Helicobacter pylori , Úlcera Péptica , Inibidores da Bomba de Prótons , Humanos , Citocromo P-450 CYP2C19/genética , Infecções por Helicobacter/tratamento farmacológico , Infecções por Helicobacter/genética , Helicobacter pylori/efeitos dos fármacos , Criança , Masculino , Feminino , Vietnã , Gastrite/tratamento farmacológico , Gastrite/microbiologia , Gastrite/genética , Úlcera Péptica/tratamento farmacológico , Úlcera Péptica/genética , Úlcera Péptica/microbiologia , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Inibidores da Bomba de Prótons/uso terapêutico , Adolescente , Pré-Escolar , Genótipo , Polimorfismo Genético , Resultado do Tratamento , Esomeprazol/uso terapêutico , Antibacterianos/uso terapêuticoRESUMO
Gastric carcinoma (GC) is a malignant tumor that is detrimental to human health. Transfer RNA-derived small RNAs are a newly identified class of noncoding small RNAs with specific biological functions that are aberrantly expressed in cancer. The aim of this study was to investigate the potential of hsa_tsr013526 as a biomarker for GC. Quantitative real-time fluorescence polymerase chain reaction was used to detect the expression level of hsa_tsr013526. The molecular characteristics of hsa_tsr013526 were verified by agarose gel electrophoresis, Sanger sequencing, and separation of nuclear and cytoplasmic RNA fractions. By testing the receiver operating characteristic (ROC) curves, the diagnostic efficiency of GC using hsa_tsr013526 was determined. Finally, we predicted the downstream of hsa_tsr013526 using functional assays and bioinformatics analysis. Serum expression of hsa_tsr013526 was higher in GC patients than in healthy donors. Serum expression showed differential changes in GC patients, gastritis patients, and healthy donors. Chi-squared tests showed that high expression of hsa_tsr013526 was significantly correlated with T stage, lymphatic metastasis, and tumor node metastasis stage. ROC curve analysis indicated that GC patients could be discriminated from healthy donors or gastritis patients based on their serum levels of hsa_tsr013526. Furthermore, hsa_tsr013526 expression was significantly reduced in postoperative GC patients (p = .0016). High expression of hsa_tsr013526 promotes gastric cancer cell proliferation, invasion, and migration. Serum hsa_tsr013526 was stable and specific, and could be used for dynamic monitoring of GC patients. Therefore, hsa_tsr013526 may be a new biomarker for the diagnosis and postoperative monitoring of GC patients.
Assuntos
Carcinoma , Gastrite , Neoplasias Gástricas , Humanos , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Neoplasias Gástricas/genética , RNA/metabolismo , Gastrite/genética , Regulação Neoplásica da Expressão GênicaRESUMO
A hallmark of infection by the pathogen Helicobacter pylori, which colonizes the human gastric epithelium, is the simultaneous activation of the classical and alternative nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathways, underlying inflammation and cell survival. Here, we report that the classical NF-κB target gene product A20 contributes to the negative regulation of alternative NF-κB signaling in gastric epithelial cells infected by H. pylori. Mechanistically, the de novo synthesized A20 protein interacts with tumor necrosis factor receptor-associated factor-interacting protein with forkhead-associated domain (TIFA) and thereby interferes with the association of TIFA with the NIK regulatory complex. We also show that alternative NF-κB activity contributes to the up-regulation of anti-apoptotic genes, such as baculoviral IAP repeat containing 2 (BIRC2), BIRC3 and B-cell lymphoma 2-related protein A1 (BCL2A1) in gastric epithelial cells. Furthermore, the observed over-expression of RelB in human gastric biopsies with type B gastritis and RelB-dependent suppression of apoptotic cell death emphasize an important role of the alternative NF-κB pathway in H. pylori infection.
Assuntos
Proteínas Reguladoras de Apoptose/metabolismo , Mucosa Gástrica/metabolismo , Infecções por Helicobacter/metabolismo , NF-kappa B/metabolismo , Proteína 3 Induzida por Fator de Necrose Tumoral alfa/metabolismo , Proteínas Reguladoras de Apoptose/genética , Proteína 3 com Repetições IAP de Baculovírus/genética , Proteína 3 com Repetições IAP de Baculovírus/metabolismo , Linhagem Celular Tumoral , Mucosa Gástrica/microbiologia , Gastrite/genética , Gastrite/metabolismo , Gastrite/microbiologia , Expressão Gênica , Técnicas de Inativação de Genes , Infecções por Helicobacter/genética , Infecções por Helicobacter/microbiologia , Helicobacter pylori/fisiologia , Interações Hospedeiro-Patógeno , Humanos , Antígenos de Histocompatibilidade Menor/genética , Antígenos de Histocompatibilidade Menor/metabolismo , NF-kappa B/genética , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Transdução de Sinais/genética , Fator de Transcrição RelA/genética , Fator de Transcrição RelA/metabolismo , Fator de Transcrição RelB/genética , Fator de Transcrição RelB/metabolismo , Proteína 3 Induzida por Fator de Necrose Tumoral alfa/genéticaRESUMO
This review highlights recent advances in the understanding of eosinophils and eosinophilic diseases, particularly eosinophilic gastrointestinal diseases during the last year. The increasing incidence of diseases marked by eosinophilia has been documented and highlighted the need to understand eosinophil biology and eosinophilic contributions to disease. Significant insight into the nature of eosinophilic diseases has been achieved using next-generation sequencing technologies, proteomic analysis, and machine learning to analyze tissue biopsies. These technologies have elucidated mechanistic underpinnings of eosinophilic inflammation, delineated patient endotypes, and identified patient responses to therapeutic intervention. Importantly, recent clinical studies using mAbs that interfere with type 2 cytokine signaling or deplete eosinophils point to multiple and complex roles of eosinophils in tissues. Several studies identified distinct activation features of eosinophils in different tissues and disease states. The confluence of these studies supports a new paradigm of tissue-resident eosinophils that have pro- and anti-inflammatory immunomodulatory roles in allergic disease. Improved understanding of unique eosinophil activation states is now poised to identify novel therapeutic targets for eosinophilic diseases.
Assuntos
Enterite/etiologia , Eosinofilia/etiologia , Eosinófilos/fisiologia , Gastrite/etiologia , Enterite/tratamento farmacológico , Enterite/genética , Enterite/imunologia , Eosinofilia/tratamento farmacológico , Eosinofilia/genética , Eosinofilia/imunologia , Esofagite Eosinofílica/etiologia , Eosinófilos/efeitos dos fármacos , Gastrite/tratamento farmacológico , Gastrite/genética , Gastrite/imunologia , Estudo de Associação Genômica Ampla , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , ImunomodulaçãoRESUMO
Stomach cancer continues to be a global health problem, ranking 5th among cancers and 4th among the causes of death from cancer in the world. Autoimmune atrophic gastritis is a chronic autoimmune disease characterized by the production of antibodies to parietal cells and intrinsic factor, followed by atrophy of the mucous membrane of the body and fundus of the stomach. Chronic autoimmune inflammation can lead to damage to the genetic apparatus of the cell and trigger a multi-stage process of carcinogenesis. Our article presents an unusual case of three different gastric tumors, including adenocarcinoma with microsatellite instability, in a patient with autoimmune gastritis.
Assuntos
Doenças Autoimunes , Gastrite Atrófica , Gastrite , Neoplasias Gástricas , Humanos , Neoplasias Gástricas/genética , Neoplasias Gástricas/patologia , Estômago/patologia , Gastrite/genética , Gastrite/patologia , Gastrite Atrófica/complicações , Gastrite Atrófica/genética , Doenças Autoimunes/diagnóstico , Doenças Autoimunes/genética , Inflamação/patologia , Doença CrônicaRESUMO
The intracellular signaling molecule TRAF6 is critical for Toll-like receptor (TLR)-mediated activation of dendritic cells (DCs). We now report that DC-specific deletion of TRAF6 (TRAF6ΔDC) resulted, unexpectedly, in loss of mucosal tolerance, characterized by spontaneous development of T helper 2 (Th2) cells in the lamina propria and eosinophilic enteritis and fibrosis in the small intestine. Loss of tolerance required the presence of gut commensal microbiota but was independent of DC-expressed MyD88. Further, TRAF6ΔDC mice exhibited decreased regulatory T (Treg) cell numbers in the small intestine and diminished induction of iTreg cells in response to model antigen. Evidence suggested that this defect was associated with diminished DC expression of interleukin-2 (IL-2). Finally, we demonstrate that aberrant Th2 cell-associated responses in TRAF6ΔDC mice could be mitigated via restoration of Treg cell activity. Collectively, our findings reveal a role for TRAF6 in directing DC maintenance of intestinal immune tolerance through balanced induction of Treg versus Th2 cell immunity.
Assuntos
Células Dendríticas/imunologia , Enterite/imunologia , Eosinofilia/imunologia , Eosinófilos/imunologia , Gastrite/imunologia , Intestinos/imunologia , Linfócitos T Reguladores/imunologia , Fator 6 Associado a Receptor de TNF/metabolismo , Células Th2/imunologia , Animais , Células Cultivadas , Células Dendríticas/microbiologia , Enterite/genética , Eosinofilia/genética , Gastrite/genética , Regulação da Expressão Gênica/genética , Regulação da Expressão Gênica/imunologia , Tolerância Imunológica/genética , Interleucina-2/genética , Interleucina-2/metabolismo , Intestinos/microbiologia , Intestinos/patologia , Ativação Linfocitária/genética , Metagenoma/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fator 88 de Diferenciação Mieloide/genética , Fator 88 de Diferenciação Mieloide/metabolismo , Transdução de Sinais/genética , Linfócitos T Reguladores/microbiologia , Fator 6 Associado a Receptor de TNF/genética , Fator 6 Associado a Receptor de TNF/imunologia , Células Th2/microbiologiaRESUMO
BACKGROUND: A persistently high methylation level in gastric mucosa after Helicobacter pylori (H. pylori) eradication is presumed to be a risk for metachronous gastric cancer (MGC); however, long-term changes in aberrant DNA methylation and histological gastritis have been unclear. Our aim was to examine changes in DNA methylation and histological gastritis according to the occurrence of MGC. METHODS: Subjects were classified into three groups: 25 patients in whom MGCs occurred after the initial endoscopic resection (ER) for early gastric cancer and H. pylori eradication (MGC group), 17 patients in whom MGC did not occur for more than 5 years after the initial ER and H. pylori eradication (non-MGC group) and 29 patients without a history of gastric cancer who succeeded in eradication more than 5 years ago (HP group). Aberrance of DNA methylation in three genes (miR-124a-3, EMX1, NKX6-1) and histological score of atrophy and intestinal metaplasia (IM) were evaluated using biopsy samples before and more than a mean of 5 years after H. pylori eradication. Also, the mean Z-score was calculated using Z-score values of the three genes. RESULTS: The methylation level of miR-124a-3 in the HP group and non-MGC group and that of EMX1 in the HP group significantly decreased in the long term after eradication. In the MGC group, H. pylori eradication did not improve aberrant methylation, and the mean Z-score significantly increased. There were significant positive correlations between methylation levels in miR-124a-3 and EMX1 and histological findings after eradication. CONCLUSIONS: A persistently high methylation level after H. pylori eradication reflected precancerous mucosal conditions and led to long-term MGC.
Assuntos
Gastrite , Infecções por Helicobacter , Helicobacter pylori , MicroRNAs , Lesões Pré-Cancerosas , Neoplasias Gástricas , Metilação de DNA , Mucosa Gástrica/patologia , Gastrite/tratamento farmacológico , Gastrite/genética , Gastrite/metabolismo , Infecções por Helicobacter/complicações , Infecções por Helicobacter/tratamento farmacológico , Infecções por Helicobacter/genética , Helicobacter pylori/genética , Humanos , MicroRNAs/metabolismo , Lesões Pré-Cancerosas/patologia , Neoplasias Gástricas/patologiaRESUMO
BACKGROUND: We investigated the association between CRP variants and chronic gastritis in H. pylori-infected patients at the allele, genotype, and haplotype levels. This was also assessed according to serum hs-CRP levels. METHODS: Study subjects consisted of 77 H. pylori-infected patients and 96 H. pylori-negative controls. Genotyping of the CRP rs1572970, rs876537, rs2794520, rs2808630, rs1130864, rs1417938, rs7553007, and rs4285692 variants were analyzed by real-time PCR. RESULTS: Significantly higher MAF and increased risk of chronic gastritis were associated with rs1130864, rs1417938, and rs7553007, which persisted after controlling for key covariates. Significant differences in the genotype distribution of rs1130864, rs1417938, and rs7553007 were also seen between H. pylori-infected patients and healthy controls. Increased risk of H. pylori-associated chronic gastritis was associated with carriage of rs1130864 C/T, and more with T/T genotype carriers, as well as with rs1417938 T/A and A/A genotype carriers. Functionally, the distribution of rs1130864 and rs1417938 genotypes were significantly different between H. pylori-infected patients and controls in the low hs-CRP (<6 mg/L) group. CRP haplotype analysis identified Block 1 (rs1572970, rs876537, rs2794520), and Block 2 (rs2808630, rs1130864, rs1417938) associated with H. pylori infection. Haplotypes ACC (Block 1) and TTA and TTT (Block 2) were positively associated with H. pylori-associated chronic gastritis with low hs-CRP levels. CONCLUSION: Altered serum levels of hs-CRP, stemming in part from the presence of specific genetic variants in CRP gene, modulate the risk of H. pylori infection.
Assuntos
Proteína C-Reativa , Gastrite , Infecções por Helicobacter , Humanos , Proteína C-Reativa/genética , Estudos de Casos e Controles , Gastrite/genética , Gastrite/complicações , Genótipo , Infecções por Helicobacter/genética , Infecções por Helicobacter/complicações , TunísiaRESUMO
AIM: The aim of this study was to study the role of key epigenetic regulators pertaining to DNA methylation and histone-modification systems in Helicobacter pylori (HP)-associated gastritis and gastric carcinogenesis. METHODS: The expression of DNA methyltransferase (DNMT-1, 3A, and 3B) and the catalytic subunit of polycomb repressive complex-2 (enhancer of zeste homolog 2 [EZH2]) in gastric carcinomas (n = 104), mucosa adjacent to carcinoma (n = 104), HP-associated gastritis (n = 95), and histologically normal mucosa (n = 31) was assessed by immunohistochemistry and qRT-PCR. RESULTS: The expression of all 3 DNMTs and EZH2 was significantly higher in HP-associated gastritis and carcinoma cases than in those with adjacent and normal mucosa. The expression of DNMT-1 and 3B was maximum in HP-associated gastritis. DNMT-3A showed higher expression in carcinoma-adjacent mucosa than in normal mucosa. Interestingly, the expression of EZH2 was higher in cases of HP-associated gastritis with metaplasia than in those without metaplasia and also in cases of intestinal type of adenocarcinoma. Significant positive correlation of EZH2 was identified with DNMT-1, DNMT-3A, and DNMT-3B. However, none of these markers was associated with survival outcome. CONCLUSION: This study establishes an important role of the key epigenetic regulators in the pathogenesis of both HP-associated gastritis and gastric carcinoma. Higher expression of all the epigenetic markers in the gastritis and their persistence in the carcinoma point toward their implications in HP-driven gastric carcinogenesis. Further, an inter-relation between the 2 arms of epigenetics, namely, DNA methylation and histone-modification in the pathogenesis of gastric carcinoma, is also documented. Given the reversibility of epigenetic phenomenon, these molecules may be of important therapeutic use.
Assuntos
Adenocarcinoma , Gastrite , Infecções por Helicobacter , Helicobacter pylori , Neoplasias Gástricas , Adenocarcinoma/patologia , DNA/análise , DNA/metabolismo , Metilação de DNA/genética , Proteína Potenciadora do Homólogo 2 de Zeste/análise , Proteína Potenciadora do Homólogo 2 de Zeste/genética , Proteína Potenciadora do Homólogo 2 de Zeste/metabolismo , Mucosa Gástrica/patologia , Gastrite/genética , Gastrite/metabolismo , Gastrite/patologia , Infecções por Helicobacter/complicações , Infecções por Helicobacter/genética , Humanos , Neoplasias Gástricas/patologiaRESUMO
BACKGROUND: Helicobacter pylori as the causative agent of the most common chronic bacterial infectious disease in human still involves a range of clinical challenging complications. In this meantime, the survey of the interaction between H. pylori virulence genes expression and its consequences on gastric antral epithelial cells is Controversial. This study surveyed the correlations between H. pylori cag Pathogenicity Island and virulence factors genes with Fgf7 gene expression as an angiogenic factor in developing gastric cancer in gastric antral epithelial cells of patients with H. pylori infection. METHOD: Gastric antral biopsy samples collected from patients out of exclusion criteria, including consumption of tobacco, alchohol and anti-H. pylori drugs, were categorized into gastric cancer (case group n:53) and gastritis (control group n:50) with and without H. pylori infection to detect changes in cDNA of fgf7 in gastric antral epithelial cells by using Real Time RT PCR. Extracted total RNA from gastric antral biopsy samples was used to synthesize cDNA for real time PCR. Furthermore, the cDNA of H. pylori cag Pathogenicity Island and other virulence factors genes were detected by using specific designed primers and simple PCR. RESULTS: Fgf7 gene expression revealed a significantly increase in gastric antral epithelial cells of gastric cancer and H. pylori-positive patients in contrast with gastritis and H. pylori-negative patients (p < 0.05). In the meanwhile, cag Pathogenicity Island and hopQ genotypes showed a positive correlation with Fgf7 gene expression (fold changes of cDNA) in gastric antral epithelial cells (p < 0.05). CONCLUSION: This study revealed an obvious correlation between Fgf7 gene expression in gastric antral epithelial cells of patients with H. pylori carcinogenic genotypes infection and some host factors including age.
Assuntos
Fator 7 de Crescimento de Fibroblastos , Gastrite , Infecções por Helicobacter , Helicobacter pylori , Neoplasias Gástricas , Proteínas de Bactérias/genética , DNA Complementar , Fator 7 de Crescimento de Fibroblastos/genética , Mucosa Gástrica/microbiologia , Mucosa Gástrica/patologia , Gastrite/genética , Expressão Gênica , Genótipo , Infecções por Helicobacter/microbiologia , Helicobacter pylori/genética , Humanos , Neoplasias Gástricas/genética , Neoplasias Gástricas/microbiologia , Fatores de Virulência/genéticaRESUMO
BACKGROUND: Circular RNAs (circRNAs) play key roles in carcinogenesis. However, the roles of circRNAs in gastric cancer are largely unknown. The aim of this study is to study the possible roles of hsa_circ_0006282 in gastric cancer. METHODS: The hsa_circ_0006282 levels in gastric cancer cell lines, 85 gastritis tissues, and 103 paired gastric cancer tissues and non-tumor tissues were first detected by quantitative real-time reverse transcription-polymerase chain reaction. RNA interference and hsa_circ_0006282 expression plasmid were further used to manipulate hsa_circ_0006282 expression in gastric cancer. Finally, biological effects of hsa_circ_0006282 were analyzed by real-time cell analysis, flow cytometry, Transwell, cell cloning assay and Western blot analysis. RESULTS: Hsa_circ_0006282 was down expressed in gastric cancer cells, gastritis tissues, and gastric cancer tissues. The abilities of cell proliferation, cell migration and resistance to apoptosis were enhanced after hsa_circ_0006282 was downregulated, while overexpression of hsa_circ_0006282 got opposite results. Besides, Western blot showed that the levels of protein kinase B (AKT) and cyclin-dependent kinase 2 (CDK2) were significantly increased and decreased after knockdown and up-regulation of hsa_circ_0006282, respectively, while phosphatase and tensin homolog deleted on chromosome ten (PTEN) was significantly opposite regulated. Finally, hsa_circ_0006282 promoted the expression of PTEN by sponging hsa-miR-136-5p. CONCLUSION: By regulating the PTEN/AKT signaling pathway through competitively binding with hsa-miR-136-5p, hsa_circ_0006282 suppresses the growth of gastric cancer.
Assuntos
Gastrite , MicroRNAs , Neoplasias Gástricas , Linhagem Celular Tumoral , Proliferação de Células/genética , Quinase 2 Dependente de Ciclina/genética , Quinase 2 Dependente de Ciclina/metabolismo , Gastrite/genética , Regulação Neoplásica da Expressão Gênica/genética , Humanos , MicroRNAs/genética , MicroRNAs/metabolismo , PTEN Fosfo-Hidrolase/genética , PTEN Fosfo-Hidrolase/metabolismo , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , RNA Circular/genética , Neoplasias Gástricas/patologia , Tensinas/genética , Tensinas/metabolismoRESUMO
Helicobacter pylori (H. pylori) is a major human pathogenic bacterium that survives in the gastric mucosa. The aim of this study is to evaluate the expression of the target gene network of miR-155-5p in H. pylori-related gastritis using a combination of public gene expression datasets and web-based platforms. To evaluate the expression of genes related to gastritis, we used two datasets from Gene Expression Omnibus (GEO) database. Then, we determined the overlaps between the predicted miR-155-5p target genes and gastritis-dysregulated GEO datasets genes; in the next step, we identified the possible miR-155-5p target-DEGs (Target-Differentially Expressed Genes). Also, we performed multiple bioinformatics analyses to identify the most important targets and downstream pathways associated with this miRNA. Using the UCSC cancer genomic browser analysis tool, we investigated the expression of hub genes in relation to gastric cancer and H. pylori infection, as well as the potential role of hub genes in gastritis, inflammation, and cancer. In this regard, 28 differentially expressed target genes of miR-155-5p were identified. Most of the captured target genes were correlated with the host immune response and inflammation. Based on the specific patterns of expression in gastritis and cancer, CD9, MST1R, and ADAM10 were candidates for the most probable targets of miR-155-5p. Although the focus of this study is primarily on bioinformatics, we think that our findings should be experimentally validated before they can be used as potential therapeutic and diagnostic tools.
Assuntos
Gastrite , Infecções por Helicobacter , Helicobacter pylori , MicroRNAs , Carcinogênese/genética , Biologia Computacional , Gastrite/genética , Perfilação da Expressão Gênica , Infecções por Helicobacter/genética , Helicobacter pylori/genética , Helicobacter pylori/metabolismo , Humanos , Inflamação/genética , MicroRNAs/genéticaRESUMO
DNMT1, as a critical enzyme affecting epigenetics through methylation of DNA cytosine-rich sequences, regulates gene expression. Exterior factors including long-term infections, in this study Helicobacter pylori infection, could change host cells' epigenetics by affecting DNMT1 gene expression. This study investigated the statistical correlation between H. pylori virulence genes and DNMT1 gene expression in gastric antral epithelial cells of gastric adenocarcinoma and gastritis patients. In a case-control study, 50 and 53 gastritis and gastric adenocarcinoma antral biopsies, including 23 and 21 patients with H. pylori infection, respectively, were collected from hospitals in the west of Iran. Having extracted total RNA from gastric biopsy samples, cDNA was synthesized and virulence genes of H. pylori were detected by using the PCR method. Relative real-time RT PCR was used to detect ΔΔCt fold changes of the DNMT1 gene expression in divided groups of patients based on H. pylori infection and clinical manifestations. The results showed that along with increasing patients' age, the DNMT1 gene expression will increase in gastric antral epithelial cells of gastric cancer patients (P ≤ 0.05). On the other hand, the biopsy samples with infection of H. pylori cagA, cagY, and cagE genotypes revealed a direct correlation along with increased DNMT1 gene expression. This study revealed the correlations of H. pylori cag pathogenicity island genes with increased DNMT1 gene expression.
Assuntos
Adenocarcinoma , Gastrite , Infecções por Helicobacter , Helicobacter pylori , Neoplasias Gástricas , Antígenos de Bactérias/genética , Antígenos de Bactérias/metabolismo , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Estudos de Casos e Controles , Citosina , DNA Complementar , Mucosa Gástrica/metabolismo , Mucosa Gástrica/patologia , Gastrite/genética , Gastrite/patologia , Expressão Gênica , Infecções por Helicobacter/genética , Helicobacter pylori/genética , Humanos , RNA , Neoplasias Gástricas/genéticaRESUMO
Helicobacter Pylori is a gram negative rod shaped microaerophilic bacterium that colonizes the stomach of approximately half the world's population. Infection with c may cause chronic gastritis which via a quite well described process known as Correas cascade can progress through sequential development of atrophic gastritis, intestinal metaplasia and dysplasia to gastric cancer. H. pylori is currently the only bacterium that is classified as a class 1 carcinogen by the WHO, although the exact mechanisms by which this bacterium contributes to gastric carcinogenesis are still poorly understood. Only a minority of H. pylori-infected patients will eventually develop gastric cancer, suggesting that host factors may be important in determining the outcome of H. pylori infection. This is supported by a growing body of evidence suggesting that the host genetic background contributes to risk of H. pylori infection and gastric carcinogenesis. In particular single nucleotide polymorphisms in genes that influence bacterial handling via pattern recognition receptors appear to be involved, further strengthening the link between host risk factors, H. pylori incidence and cancer. Many of these genes influence cellular pathways leading to inflammatory signaling, inflammasome formation and autophagy. In this review we summarize known carcinogenic effects of H. pylori, and discuss recent findings that implicate host genetic pattern recognition pathways in the development of gastric cancer and their relation with H. pylori.
Assuntos
Infecções por Helicobacter/genética , Helicobacter pylori/fisiologia , Interações Hospedeiro-Patógeno/genética , Neoplasias Gástricas/genética , Neoplasias Gástricas/microbiologia , Animais , Carcinogênese/genética , Gastrite/complicações , Gastrite/genética , Gastrite/microbiologia , Gastrite/patologia , Predisposição Genética para Doença , Infecções por Helicobacter/complicações , Infecções por Helicobacter/patologia , Helicobacter pylori/patogenicidade , Humanos , Polimorfismo de Nucleotídeo ÚnicoRESUMO
BACKGROUND: Gastric intestinal metaplasia (IM) is considered a precancerous lesion, and bile acids (BA) play a critical role in the induction of IM. Ectopic expression of HNF4α was observed in a BA-induced IM cell model. However, the mechanisms underlying the upregulation of the protein in IM cells remains to be elucidated. METHODS: The effects of HNF4α on gastric mucosal cells in vivo were identified by a transgenic mouse model and RNA-seq was used to screen downstream targets of deoxycholic acid (DCA). The expression of pivotal molecules and miR-1 was detected by immunohistochemistry and in situ hybridization in normal, gastritis and IM tissue slides or microarrays. The transcriptional regulation of HDAC6 was investigated by chromatin immunoprecipitation (ChIP) and luciferase reporter assays. RESULTS: The transgenic mouse model validated that HNF4α stimulated the HDAC6 expression and mucin secretion in gastric mucosa. Increased HDAC6 and HNF4α expression was also detected in the gastric IM cell model and patient specimens. HNF4α could bind to and activate HDAC6 promoter. In turn, HDAC6 enhanced the HNF4α protein level in GES-1 cells. Furthermore, miR-1 suppressed the expression of downstream intestinal markers by targeting HDAC6 and HNF4α. CONCLUSIONS: Our findings show that the HDAC6/HNF4α loop regulated by miR-1 plays a critical role in gastric IM. Blocking the activation of this loop could be a potential approach to preventing BA-induced gastric IM or even gastric cancer (GC).
Assuntos
Mucosa Gástrica/patologia , Fator 6 Nuclear de Hepatócito/metabolismo , Desacetilase 6 de Histona/metabolismo , MicroRNAs/metabolismo , Neoplasias Gástricas/genética , Animais , Ácidos e Sais Biliares/metabolismo , Modelos Animais de Doenças , Mucosa Gástrica/metabolismo , Gastrite/genética , Regulação da Expressão Gênica/genética , Humanos , Imuno-Histoquímica , Hibridização In Situ , Metaplasia/genética , Camundongos , Lesões Pré-Cancerosas/genética , Regiões Promotoras Genéticas/genética , Neoplasias Gástricas/patologia , Transcrição Gênica/genéticaRESUMO
BACKGROUND: Helicobacter pylori infection and heterogeneity in its pathogenesis could describe diversity in the expression of inflammatory genes in the gastric tissue. We aimed to investigate transcriptional alteration of genes linked to gastritis concerning the H. pylori infection status and its virulence factors. METHODS AND RESULTS: Biopsy samples of 12 infected and 12 non-infected patients with H. pylori that showed moderate chronic gastritis were selected for transcriptional analysis. Genotyping of H. pylori strains was done using PCR and relative expression of inflammatory genes was compared between the infected and non-infected patients using relative quantitative real-time PCR. Positive correlations between transcriptional changes of IL8 with TNF-α and Noxo1 in the infected and TNF-α with Noxo1, MMP7, and Atp4A in the non-infected patients were detected. Six distinct genotypes of H. pylori were detected that showed no correlation with gender, ethnicity, age, endoscopic findings, and transcriptional levels of host genes. Irrespective of the characterized genotypes, our results showed overexpression of TNF-α, MMP7, Noxo1, and ATP4A in the infected and IL-8, Noxo1, and ATP4A in the non-infected patients. CONCLUSIONS: A complexity in transcription of genes respective to the characterized H. pylori genotypes in the infected patients was detected in our study. The observed difference in co-regulation of genes linked to gastritis in the infected and non-infected patients proposed involvement of different regulatory pathways in the inflammation of the gastric tissue in the studied groups.
Assuntos
Gastrite/genética , Infecções por Helicobacter/genética , Helicobacter pylori/genética , Helicobacter pylori/patogenicidade , Transcriptoma/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Doença Crônica/epidemiologia , DNA Bacteriano/genética , DNA Bacteriano/isolamento & purificação , Feminino , Gastrite/epidemiologia , Genótipo , Técnicas de Genotipagem/métodos , Infecções por Helicobacter/epidemiologia , Infecções por Helicobacter/microbiologia , Humanos , Irã (Geográfico)/epidemiologia , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase em Tempo Real/métodos , Virulência , Fatores de Virulência , Adulto JovemRESUMO
BACKGROUND AND AIM: The reliable method to stratify the gastric cancer risk after Helicobacter pylori eradication remains an elusive goal. METHODS: Mass eradication of H. pylori began in 2004 in a high-risk population. After eradication, a screening program involving first-stage serological tests (pepsinogen-I, pepsinogen-II, H. pylori immunoglobin G, and gastrin-17) and second-stage endoscopic examination was launched in 2015-2018. Index lesions included gastric cancer or extensive premalignant lesions. We evaluated the performance of the serological tests to "rule in" and "rule out" the risk based on positive and negative likelihood ratios, respectively. The methylation levels of microRNA-124a-3 in the stomach were measured to indicate genetic damage. RESULTS: Among 6512 invited subjects, 3895 (59.6%) participated. Both gastrin-17 and pepsinogen tests were normal in 3560 (91.4%) subjects; 206 (5.3%) gastrin-17 and 129 (3.3%) pepsinogen tests were abnormal. Years after eradication, the severity of gastritis had fallen greatly, and extensive premalignant lesions or gastric cancer frequently occurred in newly non-atrophic-appearing mucosa. Pepsinogen testing could moderately predict atrophic gastritis (positive likelihood ratio: 4.11 [95% confidence interval: 2.92-5.77]; negative likelihood ratio: 0.14 [0.10-0.19]). Gastrin-17 was not useful (0.66 and 1.20, respectively). However, pepsinogen testing poorly predicted the index lesions (2.04 [1.21-3.42] and 0.57 [0.34-0.95]). DNA methylation levels in the post-eradication mucosa were more discriminative for predicting index lesions (3.89 [2.32-6.54] and 0.25 [0.15-0.42]). CONCLUSIONS: After eradication, pepsinogen false-negative results become more frequent because histology is improved but genetic damage may persist. Direct testing for genetic damage offers better discrimination.
Assuntos
Gastrite/tratamento farmacológico , Gastrite/microbiologia , Infecções por Helicobacter , Helicobacter pylori , Medição de Risco/métodos , Neoplasias Gástricas/etiologia , Biomarcadores/metabolismo , Metilação de DNA , Reações Falso-Negativas , Feminino , Mucosa Gástrica/metabolismo , Gastrite/diagnóstico , Gastrite/genética , Humanos , Masculino , MicroRNAs/metabolismo , Pepsinogênio A/metabolismo , Risco , Fatores de Risco , Testes Sorológicos , Índice de Gravidade de DoençaRESUMO
Helicobacter pylori (H. pylori) infection is a common disease that can cause H. pylori-associated gastritis (HAG), peptic ulcers, and gastric cancer. As a traditional Chinese medicine, Polygonum capitatum (PC) manifests its unique advantages in the prevention and treatment of complex diseases and chronic diseases, due to its ability to clear heat, detoxify and relieve pain, promote blood circulation, and remove blood stasis. In order to explore the molecular mechanism of PC for HAG, the study collected the predicted targets of active compounds, conducted functional analysis by the STRING database, collected HAG differential expression genes, and conducted KEGG enrichment analysis on the intersection of predicted targets and differential expression genes of gastritis by Cluego. The results show that PC works mainly by affecting phosphorylation of IκBα, NF-κB p65, p38MAPK, and ERK1/2 and nuclear transposition of NF-κB p65 and p-p38MAPK, which has been proved by in vivo and in vitro experiments. These results suggest that PC may act on HAG with multiple targets and pathways, and play a key role in the process of HAG treatment.